Discussion
Here we present a complicated case of reactivation TB in a patient being
treated for warm autoimmune hemolysis complicating anemia of chronic
disease and RA/SLE overlap syndrome. As far as we know, this is the
first case of reactivation TB complicated by RA/SLE overlap syndrome.
The acuity and severity of her hemolytic anemia necessitated high-dose
pulse-steroid therapy, with the unfortunate result of facilitating TB
reactivation. IGRA assays performed while the patient was on
immunosuppressive therapy were negative, and possible reactivation TB
was not considered until high-dose corticosteroid therapy began.
Pulmonary and extrapulmonary TB are common complications in the
treatment of autoimmune diseases.3 While relatively
rare in the United States (incidence of 2.7 cases per 100,000 persons in
2019)4, TB is one of the most common global etiologies
of infectious disease, infecting approximately 1.7 billion people as of
2018 (~23% of the global
population)5. Of those exposed, patients being treated
for autoimmune conditions such as SLE or RA are particularly susceptible
to active infection. Decreased production and secretion of
interferon-gamma (IFN-γ) related to therapy with corticosteroids or
TNF-a inhibitors (i.e., adalimumab) weakens phagocytotic response,
facilitating TB re-activation1,6,7. Further, the
high-dose immunosuppression blockades IFN-γ release by Th1 cells,
reducing detection of latent TB infection (LTBI) by
IGRA1,6,7.
In the acute treatment of uncontrolled rheumatological conditions, high
doses of corticosteroids or other immunosuppressants are often
first-line agents8. However, in patients with latent
TB infection, immunosuppression may only be appropriate where infection
precautions are in place. In cases with unknown TB status, a cautious
approach may be preferred, although guidelines for this specific
clinical circumstance are lacking. In our case, high-dose corticosteroid
therapy for AIHA likely facilitated TB activation, leading to the
development of necrotizing pneumonia and potentially exposing the
healthcare staff. Fortunately, there have been no healthcare-associated
TB infections to date, likely due to the absence of productive cough in
the patient and the increased infection control interventions in place
during the coronavirus pandemic.
Detection and treatment LTBI in immunocompromised patients is
complicated and often controversial9. Currently, there
are no clear universally accepted guidelines for TB detection and
screening in those being treated for autoimmune conditions with
corticosteroids. However, guidelines for LTBI in other immunocompromised
populations, such as those with solid organ transplants, may be useful.
These suggestions my vary but often recommend a two-stage screening
approach using a Tuberculin skin test (TST, positive ≥5 mm) and
IGRA10,11. However, in patients receiving inhibitors
of TNF-a and related pathways, these tests are insufficient to rule out
latent infection as TNF-a inhibitors significantly reduce these tests’
negative predictive value12.
Some studies suggest chest x-ray (CXR) may be useful as a screening tool
where immunoassays are unreliable, however its utility in diagnosing
latent infection is controversial13. Further chest CT
(CCT) may also be useful following CXR situations, with the imaging
modality detecting 89% of those with latent TB13,14.
In general, IGRA should not be used alone as a screening or diagnostic
tool in patients with suppressed Th1-immune responses and should be
interpreted with caution given their propensity for false-negative
results in these settings9. While none of these tests
are 100% sensitive, combining TST, IGRA, CXR and CT may be indicated
when attempting to rule out latent infection.
For high-risk immunocompromised individuals we recommend screening with,
IGRA, TST and CXR to increase sensitivity. If CXR is inconclusive or
there is high clinical suspicion of LTBI consider additional chest CT
imaging. If CXR or CT come back with signs of latent TB infection
(apical fibronodular lesions, calcified solitary nodule, calcified lymph
nodes, or pleural thickening), it is important to get a clear patient
history to evaluate other granulomatous disease including histoplasma
and sarcoidosis.
Consider treating patients using national
guidelines15, if IGRA or TST is positive (TST,
positive ≥5 mm) or if the patient has a history of untreated LTBI. In
patients with negative IGRA/TST and positive imaging, consider treating
those with high clinical suspicion of latent infection, including
previous incarceration, known exposure, or time spent in TB endemic
regions. Finally, consider treating anyone undergoing immunosuppressive
therapy who has had prolonged contact with an individual with active TB
regardless of immunoassay or imaging results.11
In patients with high clinical suspicion for LTBI with respiratory or
systemic syndromes, preferred diagnostic strategies include lung
imaging, sputum stains, MTB-PCR, and mycobacterial cultures as they are
unaffected by systemic immunosuppression. Of these, MTB-PCR is likely
the best choice, as highly specific results can be obtained within a
matter of hours16. However, this test is only useful
in ruling out active disease and should not be used to rule out LTBI.
Finally, isolation precautions should be considered in patients
undergoing immunosuppressive therapy with high clinical suspicion of
LTBI despite negative IRGA.